Molecular basis of myelomonocytic receptor function in HIV-1 infection ABSTRACT Harnessing the potent antiviral activities of human immunodeficiency virus (HIV)-1-specific T cells is critical to the design and development of effective HIV-1 vaccines and immunogens. To do so, a clear understanding of the precise molecular mechanisms that influence the evolution and immunoregulatory function of these cells is needed. In previous collaborative work, the PI and co-PI discovered a novel regulatory mechanism for HIV-1-specific T cells, which depends on the interactions of inhibitory and activating myelomonocytic major histocompatibility complex class I (MHC-I) receptors on dendritic cells and monocytes with HIV-1 cytotoxic T lymphocyte (CTL) epitope/MHC-I complexes. We have found (i) that binding between these molecules is both antigenic peptide- and human leukocyte antigen (HLA) allele- specific, (ii) that HIV-1 CTL escape mutations increase peptide/MHC-I (pMHC-I) affinities for inhibitory myelomonocytic receptors causing dendritic cells to become tolerogenic, and (iii) that HLA class I alleles that are known to be HIV-1-protective in humans bind activating myelomonocytic receptors with increased relative affinities. In these ways, and perhaps others, myelomonocytic receptors play key and previously unrecognized immunoregulatory roles in the adaptive immune response to HIV-1 viremia. Here, we propose that determining the molecular basis of pMHC-I/myelomonocytic receptor interactions and that the targeted manipulation of these binding events will lead to novel and improved HIV-1 vaccines and immunogens. We aim to determine a comprehensive structural, energetic and functional basis for molecular specificity in pMHC-I/myelomonocytic receptor interactions in order to provide a clear rational for including specific peptide epitopes in HIV-1 vaccines and to engineer affinity-matured myelomonocytic receptor variants to act as HIV-1 immunogens.